Our overall objective is to define critical factors in the pathogenesis of experimental amyloidosis and to prevent or delay amyloid deposition by rational dietary or therapeutic intervention. Specifically, we will determine; 1) If strain variability in amyloid susceptibility in the acute and aging mouse models resides in the mononuclear phagocytic system (MPS) degradation of amyloid precursors, possibly due to the presence of protease inhibitors; 2) If the recently discovered protective effect of bacterial endotoxic lipopolysaccharides (LPS) on amyloid deposition involves alterations in MPS activation that are reflected in cytokine profiles, oxygen radical production and other parameters of cellular function such as microtubule polymerization and activity of lysosomal enzymes; 3) If dietary manipulation (total caloric intake, protein composition, type of fatty acid and level of antioxidant) can alter the disease incidence and/or severity and whether such change can be related to macrophage protease activity. We will utilize "transfer amyloidosis", to study: a) amyloid resistance in A/J mice and in CE/J mice and b) an "amyloid enhancing factor" (AEF) extracted from brains of Alzheimer's disease patients. To achieve the specific aims we will use a) young genetically susceptible and resistant mice given azocasein by injection and b) old C57BL, A\J and SJL/J mice maintained on high casein diets. Resident Mos from susceptible and resistant mice with and without amyloidosis will be cultured with normal HDL or acute phase HDL in which SAA is a major apolipoprotein. SAA degradation will be measured subtractively by ELISA or by densitometric scanning of SAA bands on polyacrylamide gels. Cytokine profiles (both protein measured by ELISA and MRNA levels by Northern blot analysis) will be correlated with amyloid deposition. In summary, our studies converge on two key elements, MPS derived proteases and anti-proteases that may play a central role in the genesis of Alzheimer's disease in humans and azocasein-induced amyloidosis in mice. MPS function is influenced by many divergent parameters including age, dietary protein and lipid content, LPS, colchicine, and antioxidants. It is our goal to identify common elements of the MPS that lead to amyloid fibril formation, and to provide a framework from which to address the role of the MPS in other forms of amyloidosis, especially that associated with Alzheimer's disease.